The present invention is concerned with an improved method of preparing the chloromethyl ester of sulbactam ##STR1## a key intermediate in the manufacture of sultamicillin. See Bigham, U.S. Pat. Nos. 4,244,951 and Godfredsen et al., 4,342,772. Sulbactam and sultamicillin are the U.S.A.N. (U.S. Adopted Names) or generic names for penicillanic acid 1,1-dioxide and for the mixed methandiol ester with sulbactam/ampicillin, respectively.
The preparation of the ester intermediate of the formula (I) in high yield and quality by reaction of the carboxylate salt of the formula ##STR2## wherein X.sup.+ is a metal or ammonium cation, with chloroiodomethane or bromochloromethane suffers from the problem that the product is contaminated by the bis-ester of the formula ##STR3## The use of the salt of formula II, wherein X is tetrabutylammonium, by Jasys, commonly assigned U.S. Pat. No. 4,381,263, the disclosure of which is hereby incorporated by reference, improved the yield of the desired ester (I), but even here appreciable bis-ester (III) was formed [Binderup et al. Synthetic Communications, vol. 14, pages 857-864 (1984)].
More recently, Binderup et al. have employed chloromethyl chlorosulfate in place of chlorobromomethane or chloroiodomethane in reaction with the tetrabutylammonium salt of formula (II). Although the level of bis-ester is reduced thereby, use of chloromethyl chlorosulfate requires specialized equipment and handling for plant scale operations.
Commonly assigned U.S. Pat. No. 4,704,456 teaches a further variation for making the chloromethyl ester of sulbactam. That patent teaches the addition of, for example, tert-amines to improve the rate of chloromethyl ester formation, and the yield of the chloromethyl ester I (at the expense of the bis-ester (III)).
Although there are a variety of processes for producing the chloromethyl ester of sulbactam there is a continuing search in this field of art for more efficient high yielding processes.